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1.
A series of thirty-seven 1,3,5-triazine analogues have been synthesized, characterized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines such as HeLa, HepG2, A549 and MCF-7. Most of the 1,3,5-triazine analogues exhibited promising antiproliferative activity against tested cancer cell lines. Among all the synthesized compounds, 8j showed potent activity against the cancer cell lines such as HeLa, HepG2, A549 and MCF-7 with IC50 12.3 ± 0.8, 9.6 ± 0.4, 10.5 ± 1.0 and 11.7 ± 0.5 μM respectively. 8j was taken up for elaborate biological studies and the cells in the cell cycle were arrested in G2/M phase. In addition, 8j was examined for its effect on the microtubule system with a tubulin polymerization assay, immunofluorescence. 8j showed remarkable inhibition of tubulin polymerization. Molecular docking studies were also carried out to understand the binding pattern. The studies suggested that 8j has a good binding affinity of ?7.949 towards nocodazole binding site of tubulin while nocodazole has ?7.462.  相似文献   

2.
New Schiff’s base derivatives 5aj have been synthesized by reaction between 2-phenoxyquinoline-3-carbaldehydes 3aj and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide 4 in presence of nickel(II) nitrate as a catalyst in ethanol under reflux in good yield (78–92%). All compounds were tested for anticancer and inhibition of EGFR. Of the compounds studied, majority of the compounds showed effective antiproliferation and inhibition of EGFR and HER-2 activities. Compound 5h showed most effective inhibition (IC50 = 0.12 ± 0.05 μM) by binding in to the active pocket of EGFR receptor with minimum binding energy (ΔGb = −58.3691 kcal/mol). The binding was stabilized by two hydrogen bonds, two π–cation and one π–sigma interactions. Compound 5d showed most effective inhibition (IC50 = 0.37 ± 0.04 μM).  相似文献   

3.
Two series of novel kojic acid analogues (4aj) and (5ad) were designed and synthesized, and their mushroom tyrosinase inhibitory activities was evaluated. The result indicated that all the synthesized derivatives exhibited excellent tyrosinase inhibitory properties having IC50 values in the range of 1.35 ± 2.15–17.50 ± 2.75 μM, whereas standard inhibitor kojic acid have IC50 values 20.00 ± 1.08 μM. Specifically, 5-phenyl-3-[5-hydroxy-4-pyrone-2-yl-methylmercap-to]-4-(2,4-dihydroxyl-benzylamino)-1,2,4-triazole (4f) exhibited the most potent tyrosinase inhibitory activity with IC50 value of 1.35 ± 2.15 μM. The kinetic studies of the compound (4f) demonstrated that the inhibitory effects of the compound on the tyrosinase were belonging to competitive inhibitors. Meanwhile, the structure-activity relationship was discussed.  相似文献   

4.
Voltage gated sodium channels represent an important therapeutic target for a number of neurological disorders including epilepsy. Unfortunately, medicinal chemistry strategies for discovering new classes of antagonist for trans-membrane ion channels have been limited to mostly broad screening compound arrays. We have developed new sodium channel antagonist based on a propofol scaffold using the ligand based strategy of comparative molecular field analysis (CoMFA). The resulting CoMFA model was correlated and validated to provide insights into the design of new antagonists and to prioritize synthesis of these new structural analogs (compounds 4 and 5) that satisfied the steric and electrostatic model. Compounds 4 and 5 were evaluated for [3H]-batrachotoxinin-A-20-α-benzoate ([3H]-BTX-B) displacement yielding IC50’s of 22 and 5.7 μM, respectively. We further examined the potency of these two compounds to inhibit neuronal sodium currents recorded from cultured hippocampal neurons. At a concentration of 50 μM, compounds 4 and 5 tonically inhibited sodium channels currents by 59 ± 7.8% (n = 5) and 70 ± 7.5% (n = 7), respectively. This clearly demonstrates that these compounds functionally antagonize native neuronal sodium channel currents. In summary, we have shown that CoMFA can be effectively used to discover new classes of sodium channel antagonists.  相似文献   

5.
Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(am) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC50 value = 13.16 μM), 5d (IC50 value = 15.66 μM) and 5j (IC50 value = 19.16 μM) had shown good PDF inhibition activity. The compounds 5a (MIC range = 11.00–15.83 μg/mL), 5b (MIC range = 23.75–28.50 μg/mL) and 5j (MIC range = 7.66–16.91 μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range = 25–50 μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(am) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.  相似文献   

6.
A series new 2H-chromene-3-carboxamides (4a4i) and S-2H-chromene-3-carbothioates (5j5t) were synthesized and evaluated as monoamine oxidase A and B inhibitors. Among them, compound 5k (IC50 = 0.21 μM, IC50 iproniazid = 7.65 μM) showed the most activity and higher MAO-B selectivity (189.2-fold vs 1-fold) with respect to the MAO-A isoform. The need to clarify at a 3D level some important molecular aspects of discussed SAR, we undertaked a number of docking simulations to better assess. The steric effect was analyzed interms of both posing and scoring by investigating the nature of the binding interactions. The docking results of active compound 5k with hMAO-B complex indicated that conserved residue ILE 199 was important for ligand binding via Sigma–Pi interaction.  相似文献   

7.
To optimize dual receptor tyrosine kinase (RTK) and dihydrofolate reductase (DHFR) inhibition, the E- and Z-isomers of 5-[2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines (1a and 1b) were separated by HPLC and the X-ray crystal structures (2.0 and 1.4 Å, respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5 Å) were determined. The E- and Z-isomers adopt different binding modes when bound to mouse DHFR. A series of 2,4-diaminofuro[2,3-d]pyrimidines 213 were designed and synthesized using the X-ray crystal structures of 1a and 1b with DHFR to increase their DHFR inhibitory activity. Wittig reactions of appropriate 2-methoxyphenyl ketones with 2,4-diamino-6-chloromethyl furo[2,3-d]pyrimidine afforded the C8–C9 unsaturated compounds 27 and catalytic reduction gave the saturated 813. Homologation of the C9-methyl analog maintains DHFR inhibitory activity. In addition, inhibition of EGFR and PDGFR-β were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs.  相似文献   

8.
A group of novel tricyclic Δ2-isoxazolines (4b, 5b, 7ab, and 8ab) and 3-oxo-isoxazolidines (6ab and 9ab), structurally related to cytisine or norferruginine, was prepared through 1,3-dipolar cycloadditions involving suitable olefins and bromonitrile oxide. The target compounds were assayed at α4β2 and α7 neuronal acetylcholine receptors (nAChRs). The results of competition binding experiments indicated for the new derivatives a reduction of the affinity at the α4β2 subtype in comparison with the reference molecules, coupled with an overall negligible affinity at the α7 subtype. The binding mode of the bromo-Δ2-isoxazolines 4b and 7b, which were the highest affinity ligands in the series (Ki = 0.92 and 0.75 μM, respectively), was analyzed by applying a recently developed model of the α4β2 nAChRs.  相似文献   

9.
A series of coumarinyl-pyrazolinyl substituted thiazoles derivatives were synthesized and their inhibitory effects on the DPPH and mushroom tyrosinase were evaluated. The results showed that all of the synthesized compounds exhibited significant mushroom tyrosinase inhibitory activities. In particular, 3-(5-(4-(benzyloxy)-3-methoxyphenyl)-1-(4-(4-bromophenyl)thiazol-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (7j) exhibited the most potent tyrosinase inhibitory activity with IC50 value 0.00458 ± 0.00022 μM compared with the IC50 value of kojic acid is 16.84 ± 0.052 μM. The inhibition mechanism analyzed by Lineweaver–Burk plots revealed that the type of inhibition of compound 7j on tyrosinase was noncompetitive. The docking study against tyrosinase enzyme was also performed to determine the binding affinity of the compounds. The compound 7a showed the highest binding affinity (−10.20 kcal/mol) with active binding site of tyrosinase. The initial structure activity relationships (SARs) analysis suggested that further development of such compounds might be of interest. The statistics of our results endorses that compound 7j may serve as a structural template for the design and development of novel tyrosinase inhibitors.  相似文献   

10.
Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10aj, 13aj). All the compounds were evaluated for the IC50 values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC50 values of 1.1 μM, 0.92 μM and 8.77–14.3 μM. Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities.  相似文献   

11.
Seven novel diamidino 2,5-bis(aryl)thiazoles (5ag) were synthesized and evaluated against Trypanosoma brucei rhodensiense (T. b. r.) and Plasmodium falciparum (P. f.). The diamidines were obtained directly from the corresponding bis-nitriles (4ag) by the action of lithium bis(trimethylsilyl)amide. The bis-nitriles 4af were synthesized in four steps starting with the Stille coupling of 2-tributyltinthiazole with the appropriate cyanoaryl halide. The bis-nitrile 5g was obtained by the palladium facilitated coupling of the mixed tin-silyl reagent 2-trimethylsilyl-5-trimethyltinthiazole with 2-bromo-5-cyanopyridine. The amidoxime potential prodrugs 6ae, 6g were obtained by the reaction of hydroxylamine with the bis-nitriles. O-Methylation of the amidoximes gave the corresponding N-methoxyamidines 7ac, 7e, 7g. The diamidines showed strong DNA binding affinity as reflected by ΔTm measurements. Four of the diamidines 5a, 5b, 5d and 5e were highly active in vitro against P. f. giving IC50 values between 1.1 and 2.5 nM. The same four diamidines showed IC50 values between 4 and 6 nM against T. b. r. The selectivity indices ranged from 233 to 9175. One diamidine 5a produced one of four cures at an ip dose of 4 × 5 mg/kg in the STIB900 mouse model for acute African trypanosomiasis. The amidoxime and N-methoxyamidine of 5a were the only produgs to provide cures (1/4 cures) in the same mouse model on oral dosage at 4 × 25 mg/kg.  相似文献   

12.
A series of 4-dimethylamine flavonoid derivatives 5a5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC50, 1.83–33.20 μM for AChE and 0.82–11.45 μM for BChE). A Lineweaver–Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Aβ aggregation inhibitory activity at 20 μM with percentage from 25% to 48%. In addition, some compounds (5j5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent agents for the treatment of Alzheimer’s disease.  相似文献   

13.
3,3-Di(indolyl)indolin-2-ones 4a-4n were synthesized and evaluated for their in vitro α-glucosidase inhibitory activity. These newly synthesized compounds showed moderate to potent α-glucosidase inhibitory activity with IC50 range from 5.98 ± 0.11 to 145.95 ± 0.46 μM, when compared to the standard drug acarbose. Among this series of 3,3-di(indolyl)indolin-2-ones, compound 4j (5.98 ± 0.11 μM) having a 2-fluorobenzyl group on the indole ring was found to be the most active compound. Molecular docking studies showed that compound 4j have high binding affinities with the active site of α-glucosidase enzyme through hydrogen bonds, arene-cation, π-π stacking and hydrophobic interactions. This study showed these 3,3-di(indolyl)indolin-2-ones as a new class of α-glucosidase inhibitors.  相似文献   

14.
A novel series of 1-(2,4-dimethoxy-phenyl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-propenone (3) have been prepared by the Claisen–Schmidt condensation of 1-(2,4-dimethoxy-phenyl)-ethanone (1) and substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (2). Substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (2) were prepared by Vilsmeir–Haack reaction on acetophenonephenylhydrazones to offer the target compounds. The structures of the compounds were established by IR, 1H NMR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory (TNF-α and IL-6 inhibitory assays), antioxidant (DPPH free radical scavenging assay) and antimicrobial activities (agar diffusion method) against some pathogenic bacteria and fungi. Of 10 compounds screened, compounds 3a, 3c and 3g exhibited promising IL-6 inhibitory (35–70% inhibition, 10 μM), free radical scavenging (25–35% DPPH activity) and antimicrobial activities (MIC 100 μg/mL and 250 μg/mL) at varied concentrations. The structure–activity relationship (SAR) and in silico drug relevant properties (HBD, HBA, PSA, c Log P, molecular weight, EHOMO and ELUMO) further confirmed that the compounds are potential lead compounds for future drug discovery study. Toxicity of the compounds was evaluated theoretically and experimentally and revealed to be nontoxic except 3d and 3j.  相似文献   

15.
A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a5d and 8a8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (Ki = 17 nM) and 5-HT2A (Ki = 0.71 nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice.  相似文献   

16.
A combinatorial library of β-chlorovinyl chalcones (4) were synthesized by Claisen–Schmidt condensation reaction. Catalytic reaction of substituted 3-chloro-3-phenyl-propenal (2) and 1-(2,4-dimethoxy-phenyl)-ethanone or 1-(4-methoxy-phenyl)-ethanone (3) in alkaline conditions furnished the target compound 5-chloro-1-(2,4-dimethoxy-phenyl)-5-phenyl-penta-2,4-dien-1-one (4). The synthesized compounds were screened for their biological activity viz. anticancer, anti-inflammatory and antimicrobial activities. Synthesized compounds 4g and 4h revealed promising anti-inflammatory activity (66–67% TNF-α and 95–97% IL-6 inhibitory activity at 10 μM). Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Furthermore, the anticancer activity (30–40%) was shown by compounds 4d, 4e, 4h and 4b at 10 μM concentrations against ACHN followed by Calu 1, Panc1, HCT116 and H460 cell lines. Some of the compounds 4d, 4e, 4a, 4i and 4b revealed promising antimicrobial activity at MIC 50–100 μg/mL against selected pathogenic bacteria and fungi.  相似文献   

17.
Pyrazolealdehydes (4ad), Knoevenagel’s condensates (5ad) and Schiff’s bases (6ad) of curcumin-I were synthesized, purified and characterized. Hemolysis assays, cell line activities, DNA bindings and docking studies were carried out. These compounds were lesser hemolytic than standard drug doxorubicin. Minimum cell viability (MCF-7; wild) observed was 59% (1.0 μg/mL) whereas the DNA binding constants ranged from 1.4 × 103 to 8.1 × 105 M?1. The docking energies varied from ?7.30 to ?13.4 kcal/mol. It has been observed that DNA-compound adducts were stabilized by three governing forces (Van der Wall’s, H-bonding and electrostatic attractions). It has also been observed that compounds 4ad preferred to enter minor groove while 5ad and 6ad interacted with major grooves of DNA. The anticancer activities of the reported compounds might be due to their interactions with DNA. These results indicated the bright future of the reported compounds as anticancer agents.  相似文献   

18.
A new series of 1,3,5-triaryl-4,5-dihydro-1H-pyrazole 10al was designed and synthesized via cyclization of chalcones 8af with 4-amino/methanesulfonylphenylhydrazine hydrochloride 9ab. All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity, ulcerogenic liability and analgesic activity. All compounds were more COX-2 inhibitors than COX-1. While most compounds showed good anti-inflammatory activity, the trimethoxy derivatives (10a, 10b, 10g and 10h) were the most potent derivatives (ED50 = 55.78, 53.99, 67.65 and 69.20 μmol/kg respectively) in comparison with celecoxib (ED50 = 82.15 μmol/kg). Compounds 10a, 10b, 10g and 10h (ulcer index = 2.68, 1.20, 2.63 and 2.66 respectively) showed less ulceration effect than celecoxib (ulcer index = 2.90). Also, Compounds 10a, 10b, 10g and 10h showed analgesic activity higher than celecoxib and comparable to that of ibuprofen. In addition, molecular docking studies were performed for compounds 10a, 10b, 10g and 10h and the results were in agreement with that obtained from the in vitro COX inhibition assays.  相似文献   

19.
Three series of novel heterocyclic compounds (3a3g, 4a4g and 5a5g) containing benzenesulfonamide moiety and incorporating a 1,2,4-triazole ring, have been synthesized and investigated as inhibitors against four isomers of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozymes hCA I and II, compounds of two series (3a3g and 4a4g) showed Ki values in the range of 84–868 nM and 5.6–390 nM, respectively whereas compounds of series 5a5g were found to be poor inhibitors (Ki values exceeding 10,000 nM in some cases). Against hCA IX and XII, all the tested compounds exhibited excellent to moderate inhibitory potential with Ki values in the range of 2.8–431 nM and 1.3–63 nM, respectively. Compounds 3d, 3f and 4f exhibited excellent inhibitory potential against all of the four isozymes hCA I, II, IX and XII, even better than the standard drug acetazolamide (AZA) whereas compound of the series 5a5g were comparatively less potent but more selective towards hCA IX and XII.  相似文献   

20.
Early studies led to the identification of 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid methyl ester (5) with high affinity at the DAT (IC50 = 6.5 nM) and 5-HTT (Ki = 4.3 nM), while having much less affinity at the NET (Ki = 1110 nM). In the present study, we replaced the 4′-methoxy group of the 3β-phenyl ring with a bioisosteric 4′-methylthio group to give 7a. We also synthesized a number of 3β-(4-alkylthiophenyl)tropanes 7be, 3β-(4-methylsulfinylphenyl) and 3β-(4-methylsulfonylphenyl)tropane analogues 7fh as well as the 3β-(4-alkylthiophenyl)nortropane derivatives 811 to further characterize the structure–activity relationship of this type of compound for binding at monoamine transporters. With exception of the 4′-methylsulfonyl analogue 7h, all the tested compounds possessed high binding affinities at the 5-HTT. The Ki values ranged from 0.19 nM to 49 nM. The 3β-(4-methylthiophenyl)tropane 7a and its N-(3-fluoropropyl) analogue 9a and N-allyl analogue 10a are the most selective compounds for the 5-HTT over the NET (NET/5-HTT = 314–364) in the series. However, none of the compounds showed selectivity similar to 5 for both the DAT and 5-HTT relative to the NET. This study provided useful SAR information for rational design of potent and selective monoamine transporter inhibitors.  相似文献   

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